WO2022101519A1 - Female cycle diagnostics - Google Patents
Female cycle diagnostics Download PDFInfo
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- WO2022101519A1 WO2022101519A1 PCT/EP2021/081905 EP2021081905W WO2022101519A1 WO 2022101519 A1 WO2022101519 A1 WO 2022101519A1 EP 2021081905 W EP2021081905 W EP 2021081905W WO 2022101519 A1 WO2022101519 A1 WO 2022101519A1
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- WIPO (PCT)
- Prior art keywords
- resistance
- data points
- biomarker
- status
- determining
- Prior art date
Links
- 238000000034 method Methods 0.000 claims abstract description 59
- 239000000090 biomarker Substances 0.000 claims abstract description 45
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- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 3
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- 229930182833 estradiol Natural products 0.000 claims description 3
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- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/0012—Ovulation-period determination
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
- A61B5/053—Measuring electrical impedance or conductance of a portion of the body
- A61B5/0538—Measuring electrical impedance or conductance of a portion of the body invasively, e.g. using a catheter
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
- A61B5/4261—Evaluating exocrine secretion production
- A61B5/4294—Evaluating exocrine secretion production vaginal secretions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/43—Detecting, measuring or recording for evaluating the reproductive systems
- A61B5/4306—Detecting, measuring or recording for evaluating the reproductive systems for evaluating the female reproductive systems, e.g. gynaecological evaluations
- A61B5/4318—Evaluation of the lower reproductive system
- A61B5/4331—Evaluation of the lower reproductive system of the cervix
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/43—Detecting, measuring or recording for evaluating the reproductive systems
- A61B5/4306—Detecting, measuring or recording for evaluating the reproductive systems for evaluating the female reproductive systems, e.g. gynaecological evaluations
- A61B5/4318—Evaluation of the lower reproductive system
- A61B5/4337—Evaluation of the lower reproductive system of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/0012—Ovulation-period determination
- A61B2010/0016—Ovulation-period determination based on measurement of electric currents, e.g. conductivity tests
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/0012—Ovulation-period determination
- A61B2010/0019—Ovulation-period determination based on measurement of temperature
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/02—Details of sensors specially adapted for in-vivo measurements
- A61B2562/0271—Thermal or temperature sensors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/16—Details of sensor housings or probes; Details of structural supports for sensors
- A61B2562/164—Details of sensor housings or probes; Details of structural supports for sensors the sensor is mounted in or on a conformable substrate or carrier
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
- A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
Definitions
- the present disclosure relates to a method and a system for monitoring of the menstrual cycle of a female.
- the present disclosure relates to a method and a system for determining the hormone status and/or the fertility status of a female.
- Fertility is one of the most important health care aspects in the society. Fertility and fecundity are associated with several factors such as, among others psychological, environmental and chemical factors. The increasing influence of environmental factors and knowledge about the associated risks to such factors are leading to a growing need for methods by which the fertility of the population can be assessed without significant encroachment of the personal circumstances of test persons. Measurement methods systems for the evaluation of the menstrual cycle and fertility of women are much needed that will not encroach on their daily routines.
- Determining fertility either for family planning or for contraception is a critical approach of the female health care system and precise determination of ovulation is required.
- the menstrual cycle is a complex interplay of many hormones and other body functions. So far, some indirect methods to determine the ovulation in women are based on serum hormone levels or measurement of the basal body temperature. The method using serum hormone levels is reliable in respect of available hormones in the body but the employment of laboratory diagnostic methods that are required for these measurements in urine leads to substantial costs.
- the method comprises determining a continuous series of resistance data points relating to a resistance in a vagina of the female, identifying, in the continuous series of resistance data points, if a rise in resistance occurs that is higher than a predetermined value, and correlating the rise in electrical resistance to an increase of a first biomarker in the female.
- the method relates to determination of a status of a female cycle.
- the method comprises determining a continuous series of temperature data points relating to a body temperature of the female and determining a status of a second biomarker based on the continuous series of temperature data points.
- the method further comprises determining a continuous series of resistance related data points relating to an electrical resistance in a vagina of the female, and determining a status of a first biomarker based on the continuous series of resistance related data points.
- the method further comprises correlating the status of the first biomarker with the status of the second biomarker and indicating the status of the female cycle based on the correlation between the status of the first biomarker and the status of the second biomarker.
- the disclosure relates to a system and a measurement device with at least one sensor device comprising a temperature sensor for determining and recording a series of temperature data points relating to a body temperature of the female and an electrical resistance sensor for determining and recording a series of resistance data points in the vagina of the female.
- the system comprises an analysing tool for analysing the series of temperature data points and for analysing the series of resistance data points, wherein the series of temperature data points and the series of resistance data points are transferred from the sensor device to the analysing tool wherein the system or the measurement device is configured to carry out one of the methods described above.
- the disclosure relates to a method for determining a status of a biomarker in an intrabody medium using a sensor device.
- the method comprises the steps of charging a capacitor in the sensor device, discharging the capacitor via two electrodes, wherein the electrodes are in contact with the intrabody medium, determining a discharging time by which the charge of the capacitor is below a predetermined value, and correlating the discharging time to an electrical resistance of the intrabody medium.
- the disclosure relates to a sensor device for determining a status of a biomarker in an intrabody medium.
- the sensor device comprises a capacitor in the sensor device, a first electrode connected to the first side of the capacitor and a second electrode connected to a second side fo the capacitor.
- the sensor device further comprises a microcontroller for determining a discharging time of the capacitor when the capacitor is discharged over an intrabody resistance between the first electrode and the second electrode.
- the fertility states may relate to at least one of menstrual cycle diagnostics, CFG score, contraception and pregnancy or any combination thereof.
- Fig. 1 shows a pessary that may be used for obtaining impedance data and optional temperature data in relation with the present disclosure
- Fig. 2 shows a circuit model representing one example of a resistance measurement
- Fig. 3 shows examples of voltage curves obtained by a measurement circuit indicated in Fig. 2;
- Fig. 4 a and b show examples for continuous data curves of temperature data points and impedance data points, respectively;
- Fig. 5 shows an example of typical estrogen and progesterone concentrations during a biphasic human female cycle
- Fig. 6 shows a comparison of temperature curves and impedance curves for a biophysic and a monophasic cycle.
- the present disclosure relates in one example to a method and a system for determining a status of a biomarker in an intrabody medium and/or a female.
- the method and system comprises determining a continuous series of conductance or resistance data points relating to an electrical conductance or electrical resistance in a vagina of the female.
- Conductance or resistance data points may relate to at least one of electrical conductance or electrical resistance in the vaginal mucus, in vaginal tissue, or any combination thereof.
- resistance will be used herein for simplicity to describe both, electrical resistance or the related electrical conductance. It is understood that the conductance may be obtained via resistance measurements or that determination of conductance can replace determination of resistance.
- the method may further comprise identifying, in the continuous series of resistance data points, if a significant change in resistance occurs.
- the significant change in resistance may, for example, be a rise in resistance that is higher than a predetermined value.
- the significant change may also be a rise in resistance that last for more than a pre-determined period in time.
- the significant change can be a drop or decay in resistance or a specific pattern in the series of resistance data points.
- the significant change in resistance is correlated to a change in a first biomarker.
- a rise in resistance is correlated to a body response to a rise in estrogen level during the female cycle.
- the response of the body to estrogen may be the first biomarker in this example.
- the response of the body to an increased level of estrogen may be an increased water concentration in the intrabody medium in the vagina, e.g. in the cervical mucus and/or in vaginal tissue, which in turn can be measured by an increased resistance.
- a rise in resistance indicate a higher resistivity of the intrabody medium in the vagina that may origin from an increased water concentration in the cervical mucus and/or in vaginal issue which can be a pre-ovulatory response of the body to an increased estrogen level.
- the inventors have found that this response of the body can be directly measured by continuous determination of electrical resistance in the vagina.
- the increase in resistance indicates a pre-ovulatory estrogen increase that in turn indicates that ovulation may occur within short. This may indicate the beginning of a fertility window.
- the estrogen level may be an estradiol level, for example in a normal bi-phasic cycle in which ovulation occurs.
- the estrogen level may be also partially or completely be influenced by other estrogens such as estriol.
- Estriol may be present in the beginning or during pregnancy and may also give rise to an increased resistance.
- resistance may be determined by impedance measurements at one or more frequencies. Impedance measurements may provide additional information in addition to the resistance in the vagina. The inventors have found, however, that determination of a relative change of resistance (or conductivity) is sufficient for the determination of estrogen level in the body.
- the present description also relates to a sensor device and a system comprising such a sensor device that is configured to carry out the method described herein.
- the method comprises determining a continuous series of temperature data points relating to a body temperature of the female and determining a status of a second biomarker based on the continuous series of temperature data points.
- the status of the second biomarker is correlated to the status of the first biomarker.
- the status of the female cycle or other information about the correlation between the first biomarker status and the second biomarker status may be obtained.
- the second biomarker may be a response of the body to progesterone, i.e. a change in the temperature curve as a response to an increased or reduced progesterone level.
- the correlation between the first biomarker and the second biomarker may be a rise in the estrogen response while the temperature data remain unchanged indicating a pre-ovulatory estrogen release shortly before ovulation. This may be an indication that ovulation may occur within short. A subsequent rise in temperature or decrease in temperature amplitude indicates the response to a post-ovulatory progesterone release. This sequence indicates that ovulation occurred and that the fertility window is open. This sequence is also an indication for a bi-phasic cycle.
- hormones may be present in blood but one or more of these hormones are not functional, i.e. because binding of the hormone to receptors can not occur or the binding of the hormone cannot trigger the corresponding events and response.
- the method and system of the present disclosure detects the effects or the body response to the hormone and indicates the functionality of the endocrinological system.
- the methods of the present disclosure may further comprise determining a series of pH-values.
- a variation in the pH-values may be identified and the variation in the pH- values may be correlate to the variation of resistance and/or the variation of temperature.
- a variation in pH may indicate an inflammation in the vagina.
- a continuous series of data points e.g. a continuous series of resistance data points and/or a continuous series of temperature data points is a series of data points measured in pre-determined time intervals.
- the time intervals for resistance measurements and for temperature measurement can vary. It is advantageous to take measure in time intervals that are shorter than the usual change in the response to a triggering event such as the release of a hormone in the body. For example, in the case of an increase of impedance in response to a pre-ovulatory release or estrogen, a measurement every 5 minutes, every 10 minutes or even every 30 or 60 minutes may be sufficient to obtain a series of data points with an increase of impedance for more than 6 hours, more than 12 hours or even more than 24 hours in response to the estrogen release.
- the time intervals can depend on the body reaction time in response to the triggering event.
- Data of a plurality of cycles of the same female may be compared to each other to obtain information on the current cycle, for example to determine fertility or the fertility window in the current cycle.
- the current cycle data may be compared to cycle from other females.
- An intrabody sensor device may be used for determining the continuous series of resistance data points.
- the sensor may be implemented in a pessary that is in use placed in the vagina. In other examples, the sensor device may be placed in other body orifices to obtain information about other body parameters. The same sensor device may be used for determining temperature data points. Body core temperature may be obtained with use of pessary or another intravaginal device. Temperature data points, however, may also obtained from other temperature sensors, such as temperature plaster or other sensors arranged on the skin of a user.
- Resistance data points for the series of resistance data points may be obtained by a method and a system comprising the steps of charging a capacitor in a sensor device.
- the capacitor is connected to a first electrode and a second electrode that are both in use in contact with the vagina.
- the cervical mucus, the vaginal tissue of the female or a combination thereof has a resistivity depending on biological parameters.
- a parameter relating to the resistivity can be measured by discharging the capacitor via the two electrodes and determining a discharging time by which the charge or voltage of the capacitor is below a predetermined value. The discharging time may be correlated to an electrical resistance of the vagina.
- Data points can be obtained from a single discharging event.
- the determination of a resistance data point may have a higher reliability if the measurement is repeated several times, for example 4 to 20 times within a short time interval.
- the capacitor may be charged with different or alternating polarity from measurement to measurement. Data corrections may be applied to exclude unreasonable or invalid results.
- An average value may be determined from the plurality of measurements to obtain a single resistance data point.
- a series of resistance data points may be formed from a plurality of single resistance data points taken in pre-determined time intervals over an extended period in time.
- the extended period may be several days or weeks. Comparing resistance data points can indicate a change, in particular a rise or drop in resistivity.
- a sensor device for a vaginal measurement may comprise a capacitor, a first electrode, a second electrode and a microcontroller for determining a discharging time of the capacitor when the capacitor is discharged.
- the sensor device can be part of a flexible pessary.
- the body core temperature and/or the impedance may be measured by one or more sensors placed in the vaginal channel of the female.
- the body core temperature may also be measured in other body orifices. Measurements of temperature and impedance in body orifices are the most reliable measurements of a human or animal and is by far more precise than measurements on other places, for example on the skin. Devices carried on the wrist or sensor plaster devices are often influenced by external or environmental conditions and are less reliable.
- An example of a sensor device for measuring the body core temperature and the impedance inside the body is shown in Figs la to lc and described in US 2013/0237771 (EP 2567680) the content of which is incorporated herein by reference.
- the sensor device 10 may have the form of a pessary or may be attached to a pessary 20 placed in the vaginal channel of the female.
- a temperature sensor can measure the actual body core temperature of the user inside the vaginal channel.
- An impedance or resistance sensor in the sensor device 10 can measure the resistance or the impedance in the vagina.
- the temperature sensor and the resistance sensor are able to measure and record circamensual (30 days and more) a series of body core temperature data points and/or a series of resistance data points, respectively.
- the sensor device attached to the pessary provides high comfort for the user and high data reliability and is therefore advantageous for the method and system of the present disclosure.
- the method and system of the present disclosure may be used with other sensors that measure continuous series of resistance data points and, optionally, of body core temperature data points inside the body or measure series of temperature values at other places of the body even though the temperature measurement in other places may be less precise.
- the resistance sensor comprises at least two resistance electrodes El, E2 that are arranged in the sensor device 10.
- the resistance electrodes may be arranged at the surfaces of the sensor device and may be configured to come in contact with the cervical mucus, when the pessary is placed in the vagina.
- the electrodes may be made from a metal material. Gold or other inert metals may be applied.
- the electrodes may used for resistance and/or for impedance measurements.
- Fig. 2 shows an example of a circuit diagram that can be used for measuring the resistance.
- the sensor device 10 comprises a microcontroller 12 that is connected to a capacitor C by contact Cl and contact C2.
- the capacitor C can be charged in both polarities depending on the polarity applied to contact Cl and C2.
- a microcontroller voltage of 3V can be used to directly charge the capacitor C.
- the microcontroller may control an external power supply to charge the capacitor C to higher voltages.
- the charged capacitor C is connected to both electrodes El and E2 such that the capacitor can discharge via the electrodes El and E2 if both electrodes are connected.
- an electrical connection is present via cervical mucus, other body fluids or intrabody media, the electrodes are connected to. These intrabody media have a certain resistance Rb that can be measured by determining a discharging time with the microcontroller 12.
- Fig. 3 shows examples of corresponding discharging curves.
- the capacitor C is charged with different polarities to a max voltage Uc and subsequently an average discharging time is recorded.
- the decay in voltage is an exponential decay and a threshold voltage is defined.
- the time is determined by which the capacitance voltage drops below the threshold voltage.
- the threshold voltage is 1/3 of the maximal voltage Uc but other thresholds may be used as well.
- the measurement may be repeated several times and with different polarities to obtain an average discharging value. Measured values with unreasonable results may be removed or other correction methods may be applied.
- resistance data points are taken in pre-determined time intervals and a series of resistance data points is formed from consecutive data points.
- a continuous resistance data curve can be evaluated from these resistance data points representing the actual resistance in the vagina of the female.
- a series of temperature data points and, optionally, a continuous temperature data curve is evaluated from the temperature data points.
- FIGS. 4a and 4b Examples for continuous data curves of temperature data points and resistance data points are shown in Figures 4a and 4b, respectively. 288 temperature data points per day were measured and recorded continuously every 5 minutes over a menstrual cycle (about 30 days or more). The pre-determined time interval is 5 minutes in this example but can be varied. Resistance data points were measured and recorded in the same time interval as the temperature data points for convenience.
- Figure 4 a and b show an example of a biphasic female cycle in which ovulation occurred.
- Fig. 4a shows a series of temperature data points that vary during day and night times and that depend not only on the hormone status, but also on other activities and health parameters of the user. Several approaches were made to derive basal temperatures from temperature data curves.
- Fig. 4b shows an example of impedance data measured simultaneously to the temperature curve of Fig. 2a at the same place in the vagina channel.
- the impedance may relate to the impedance of the cervical mucus or to vaginal tissue or to a combination thereof.
- the impedance data of Fig. 4b show a significant increase on day 7 and 8.
- the impedance is constantly increasing over more than 24 hrs. to a level far above the usual fluctuations.
- the inventors found that this increase is correlated to the distribution of estrogen, in particular of estradiol, into the body.
- the presence of estrogen may increase the amount or water in the cell or which may alter the structure of vaginal secrets like the cervical mucus which, in turn, alter the impedance.
- the impedance is measured in the vagina, which is a measure for the effect of estrogen in the vagina.
- the present disclosure provides a method for determining an estrogen response in the vagina.
- impedance increases, in the particular example shown, about 24 hours prior to the release of progesterone, indicating that estrogen was released and that ovulation is probable to occur shortly after.
- the time window between increase of impedance and the response to progesterone may differ from cycle to cycle and may differ from woman to woman.
- the time window can be 24 hours or even less an can be longer up to several days in other examples.
- the increase in impedance indicates that ovulation will occur within short. If the temperature is evaluated in parallel, a low temperature may indicate the window of ovulation and a rise in temperature or reduction in temperature amplitude may indicate the increase of progesterone after ovulation.
- Fig. 5 shows an example of text book curves showing a typical concentration of the hormones estrogen, progesterone, LH, and FSH in a female. This figure indicates the amount of progesterone present in the body.
- the impedance and temperature data shown in Figs. 4 indicate the actual response of the female body to the present of the hormones. That means that only active hormones are measured. Hormones that, for example, if hormones can not bind to corresponding receptors or in cases of a disfunction of the receptors or subsequent signal cascades, the presence of estrogen will have no or only reduced effect. This may be detected by the present disclosure and appropriate treatment may be triggered.
- Fig. 6 shows a comparison of different cycle types.
- the left hand figures indicate a normal biphasic cycle where ovulation occurred. This cycle is similar to the cycle shown in Fig. 4.
- the right-hand figures show temperature date and impedance data (lower curve) for a monophasic cycle, i.e. a cycle in which no ovulation occurs. In this example, no increase in impedance is observed indicating that no estrogen was released or that release of estrogen did not have any effect.
- Temperature data in the upper curve do not show a rise in temperature or a decrease in temperature amplitude indicating that no progesterone was released. In this case no ovulation occurred.
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Abstract
The disclosure relates to a method and a system for determining the fertility status of a female and/or the status of a biomarker in a mammal or human being. The method comprises determining a continuous series of resistance data points relating to a resistance in a vagina of the female, identifying, in the continuous series of resistance data points, if a rise in resistance occurs that is higher than a predetermined value, and correlating the rise in resistance to an increase of a first biomarker in the female.
Description
Description
Title: Female Cycle Diagnostics
Field of the invention
[0001] The present disclosure relates to a method and a system for monitoring of the menstrual cycle of a female. In particular, the present disclosure relates to a method and a system for determining the hormone status and/or the fertility status of a female.
Introduction
[0002] Fertility is one of the most important health care aspects in the society. Fertility and fecundity are associated with several factors such as, among others psychological, environmental and chemical factors. The increasing influence of environmental factors and knowledge about the associated risks to such factors are leading to a growing need for methods by which the fertility of the population can be assessed without significant encroachment of the personal circumstances of test persons. Measurement methods systems for the evaluation of the menstrual cycle and fertility of women are much needed that will not encroach on their daily routines.
[0003] Determining fertility either for family planning or for contraception is a critical approach of the female health care system and precise determination of ovulation is required. The menstrual cycle is a complex interplay of many hormones and other body functions. So far, some indirect methods to determine the ovulation in women are based on serum hormone levels or measurement of the basal body temperature. The method using serum hormone levels is reliable in respect of available hormones in the body but the employment of laboratory diagnostic methods that are required for these measurements in urine leads to substantial costs.
[0004] Otherwise, a postovulatory rise in the temperature of about 0.5°C (+/- 0-1 °C) has been documented in the evaluation of the course of the menstrual cycle. This temperature
rise is due to the circadian variations of the body core temperature amount to ± 0.5 ^c. Conventional methods aim to identify and determine this variation in body core temperature. These conventional methods are based on the estimation of a basal temperature, the lowest temperature during a day. Due to many other influences on the body temperature, the basal temperature is mostly measured in the morning after wakeup and involves an inconvenient temperature measurement right after waking up. The temperature measurement must then be repeated every day. A change in this basal temperature is used as an indication for ovulation. This method is not very reliable.
[0005] There is a need to provide a more reliable determination of the menstrual cycle of a female and to determine the actual fertility status of the woman or female.
Summary of the invention
[0006] The present disclosure suggests a method and a system for determining the status of a biomarker in a female mammal or human being as outlined in the independent claims. Optional additional features are presented in the dependent claims.
[0007] In one aspect, the method comprises determining a continuous series of resistance data points relating to a resistance in a vagina of the female, identifying, in the continuous series of resistance data points, if a rise in resistance occurs that is higher than a predetermined value, and correlating the rise in electrical resistance to an increase of a first biomarker in the female.
[0008] In another alternative or additional aspect, the method relates to determination of a status of a female cycle. The method comprises determining a continuous series of temperature data points relating to a body temperature of the female and determining a status of a second biomarker based on the continuous series of temperature data points. The method further comprises determining a continuous series of resistance related data points relating to an electrical resistance in a vagina of the female, and determining a status of a first biomarker based on the continuous series of resistance related data points. The
method further comprises correlating the status of the first biomarker with the status of the second biomarker and indicating the status of the female cycle based on the correlation between the status of the first biomarker and the status of the second biomarker.
[0009] In yet another alternative or additional aspect, the disclosure relates to a system and a measurement device with at least one sensor device comprising a temperature sensor for determining and recording a series of temperature data points relating to a body temperature of the female and an electrical resistance sensor for determining and recording a series of resistance data points in the vagina of the female. The system comprises an analysing tool for analysing the series of temperature data points and for analysing the series of resistance data points, wherein the series of temperature data points and the series of resistance data points are transferred from the sensor device to the analysing tool wherein the system or the measurement device is configured to carry out one of the methods described above.
[0010] In yet another aspect, the disclosure relates to a method for determining a status of a biomarker in an intrabody medium using a sensor device. The method comprises the steps of charging a capacitor in the sensor device, discharging the capacitor via two electrodes, wherein the electrodes are in contact with the intrabody medium, determining a discharging time by which the charge of the capacitor is below a predetermined value, and correlating the discharging time to an electrical resistance of the intrabody medium.
[0011] In a further aspect, the disclosure relates to a sensor device for determining a status of a biomarker in an intrabody medium. The sensor device comprises a capacitor in the sensor device, a first electrode connected to the first side of the capacitor and a second electrode connected to a second side fo the capacitor. The sensor device further comprises a microcontroller for determining a discharging time of the capacitor when the capacitor is discharged over an intrabody resistance between the first electrode and the second electrode.
[0012] In some examples, the fertility states may relate to at least one of menstrual cycle diagnostics, CFG score, contraception and pregnancy or any combination thereof.
Description of the figures
[0013] The invention may be better understood when reading the detailed description of examples of the present disclosure which is given with respect to the accompanying figures in which:
Fig. 1 shows a pessary that may be used for obtaining impedance data and optional temperature data in relation with the present disclosure;
Fig. 2 shows a circuit model representing one example of a resistance measurement;
Fig. 3 shows examples of voltage curves obtained by a measurement circuit indicated in Fig. 2;
Fig. 4 a and b show examples for continuous data curves of temperature data points and impedance data points, respectively;
Fig. 5 shows an example of typical estrogen and progesterone concentrations during a biphasic human female cycle; and
Fig. 6 shows a comparison of temperature curves and impedance curves for a biophysic and a monophasic cycle.
Detailed description
[0014] Examples of the present disclosure will now be described in more detail. It is to be understood that the described examples and the examples shown in the figures are purely illustrative and a person skilled in the art will amend the examples according to requirements and as will best fit to an application. It is not necessary to implement all features shown in an example and a person skilled in the art will combine features shown
or described with respect to one figure with examples shown in other figures or described elsewhere in the present disclosure.
[0015] The present disclosure relates in one example to a method and a system for determining a status of a biomarker in an intrabody medium and/or a female.
[0016] In one aspect, the method and system comprises determining a continuous series of conductance or resistance data points relating to an electrical conductance or electrical resistance in a vagina of the female. Conductance or resistance data points may relate to at least one of electrical conductance or electrical resistance in the vaginal mucus, in vaginal tissue, or any combination thereof.
[0017] The term resistance will be used herein for simplicity to describe both, electrical resistance or the related electrical conductance. It is understood that the conductance may be obtained via resistance measurements or that determination of conductance can replace determination of resistance.
[0018] The method may further comprise identifying, in the continuous series of resistance data points, if a significant change in resistance occurs. The significant change in resistance may, for example, be a rise in resistance that is higher than a predetermined value. The significant change may also be a rise in resistance that last for more than a pre-determined period in time. In other examples the significant change can be a drop or decay in resistance or a specific pattern in the series of resistance data points.
[0019] The significant change in resistance is correlated to a change in a first biomarker. For example, the inventors found that a rise in resistance is correlated to a body response to a rise in estrogen level during the female cycle. The response of the body to estrogen may be the first biomarker in this example.
[0020] The response of the body to an increased level of estrogen may be an increased water concentration in the intrabody medium in the vagina, e.g. in the cervical mucus and/or in vaginal tissue, which in turn can be measured by an increased resistance. A rise
in resistance indicate a higher resistivity of the intrabody medium in the vagina that may origin from an increased water concentration in the cervical mucus and/or in vaginal issue which can be a pre-ovulatory response of the body to an increased estrogen level. The inventors have found that this response of the body can be directly measured by continuous determination of electrical resistance in the vagina. In other words, the increase in resistance indicates a pre-ovulatory estrogen increase that in turn indicates that ovulation may occur within short. This may indicate the beginning of a fertility window.
[0021] The estrogen level may be an estradiol level, for example in a normal bi-phasic cycle in which ovulation occurs. The estrogen level may be also partially or completely be influenced by other estrogens such as estriol. Estriol may be present in the beginning or during pregnancy and may also give rise to an increased resistance.
[0022] In one example, resistance may be determined by impedance measurements at one or more frequencies. Impedance measurements may provide additional information in addition to the resistance in the vagina. The inventors have found, however, that determination of a relative change of resistance (or conductivity) is sufficient for the determination of estrogen level in the body.
[0023] The present description also relates to a sensor device and a system comprising such a sensor device that is configured to carry out the method described herein.
[0024] In another example the method comprises determining a continuous series of temperature data points relating to a body temperature of the female and determining a status of a second biomarker based on the continuous series of temperature data points. The status of the second biomarker is correlated to the status of the first biomarker. The status of the female cycle or other information about the correlation between the first biomarker status and the second biomarker status may be obtained. The second biomarker may be a response of the body to progesterone, i.e. a change in the temperature curve as a response to an increased or reduced progesterone level.
[0025] The correlation between the first biomarker and the second biomarker may be a rise in the estrogen response while the temperature data remain unchanged indicating a pre-ovulatory estrogen release shortly before ovulation. This may be an indication that ovulation may occur within short. A subsequent rise in temperature or decrease in temperature amplitude indicates the response to a post-ovulatory progesterone release. This sequence indicates that ovulation occurred and that the fertility window is open. This sequence is also an indication for a bi-phasic cycle.
[0026] If one or more of these events do not occur, this may be an indication that one or more endocrinal functions did not occur in that cycle. This can be due to an endocrinological disorder, the quantity and/or quality of the released hormones progesterone and estrogen. For example, in some cases hormones may be present in blood but one or more of these hormones are not functional, i.e. because binding of the hormone to receptors can not occur or the binding of the hormone cannot trigger the corresponding events and response. The method and system of the present disclosure detects the effects or the body response to the hormone and indicates the functionality of the endocrinological system.
[0027] Monitoring the change in resistance and the temperature enables to follow the status of the female cycle.
[0028] The methods of the present disclosure may further comprise determining a series of pH-values. A variation in the pH-values may be identified and the variation in the pH- values may be correlate to the variation of resistance and/or the variation of temperature. A variation in pH may indicate an inflammation in the vagina.
[0029] A continuous series of data points, e.g. a continuous series of resistance data points and/or a continuous series of temperature data points is a series of data points measured in pre-determined time intervals. The time intervals for resistance measurements and for temperature measurement can vary. It is advantageous to take measure in time intervals that are shorter than the usual change in the response to a triggering event such as the
release of a hormone in the body. For example, in the case of an increase of impedance in response to a pre-ovulatory release or estrogen, a measurement every 5 minutes, every 10 minutes or even every 30 or 60 minutes may be sufficient to obtain a series of data points with an increase of impedance for more than 6 hours, more than 12 hours or even more than 24 hours in response to the estrogen release. In other words, the time intervals can depend on the body reaction time in response to the triggering event.
[0030] Data of a plurality of cycles of the same female may be compared to each other to obtain information on the current cycle, for example to determine fertility or the fertility window in the current cycle. In other applications, the current cycle data may be compared to cycle from other females.
[0031] An intrabody sensor device may be used for determining the continuous series of resistance data points. The sensor may be implemented in a pessary that is in use placed in the vagina. In other examples, the sensor device may be placed in other body orifices to obtain information about other body parameters. The same sensor device may be used for determining temperature data points. Body core temperature may be obtained with use of pessary or another intravaginal device. Temperature data points, however, may also obtained from other temperature sensors, such as temperature plaster or other sensors arranged on the skin of a user.
[0032] Resistance data points for the series of resistance data points may be obtained by a method and a system comprising the steps of charging a capacitor in a sensor device. The capacitor is connected to a first electrode and a second electrode that are both in use in contact with the vagina. The cervical mucus, the vaginal tissue of the female or a combination thereof has a resistivity depending on biological parameters. A parameter relating to the resistivity can be measured by discharging the capacitor via the two electrodes and determining a discharging time by which the charge or voltage of the capacitor is below a predetermined value. The discharging time may be correlated to an electrical resistance of the vagina.
[0033] Data points can be obtained from a single discharging event. The determination of a resistance data point may have a higher reliability if the measurement is repeated several times, for example 4 to 20 times within a short time interval. The capacitor may be charged with different or alternating polarity from measurement to measurement. Data corrections may be applied to exclude unreasonable or invalid results. An average value may be determined from the plurality of measurements to obtain a single resistance data point.
[0034] A series of resistance data points may be formed from a plurality of single resistance data points taken in pre-determined time intervals over an extended period in time. The extended period may be several days or weeks. Comparing resistance data points can indicate a change, in particular a rise or drop in resistivity.
[0035] A sensor device for a vaginal measurement may comprise a capacitor, a first electrode, a second electrode and a microcontroller for determining a discharging time of the capacitor when the capacitor is discharged. The sensor device can be part of a flexible pessary.
[0036] While the method and the system are been described in relation to a resistance measurement in the vagina that may be used to determine a change in estrogen level, the principles of the method and the system may be equally applied any intrabody medium and may be used in other body orifices of animals and human beings.
[0037] The body core temperature and/or the impedance may be measured by one or more sensors placed in the vaginal channel of the female. The body core temperature may also be measured in other body orifices. Measurements of temperature and impedance in body orifices are the most reliable measurements of a human or animal and is by far more precise than measurements on other places, for example on the skin. Devices carried on the wrist or sensor plaster devices are often influenced by external or environmental conditions and are less reliable.
[0038] An example of a sensor device for measuring the body core temperature and the impedance inside the body that may be used with the present disclosure is shown in Figs la to lc and described in US 2013/0237771 (EP 2567680) the content of which is incorporated herein by reference. The sensor device 10 may have the form of a pessary or may be attached to a pessary 20 placed in the vaginal channel of the female. A temperature sensor can measure the actual body core temperature of the user inside the vaginal channel. An impedance or resistance sensor in the sensor device 10 can measure the resistance or the impedance in the vagina. The temperature sensor and the resistance sensor are able to measure and record circamensual (30 days and more) a series of body core temperature data points and/or a series of resistance data points, respectively. The sensor device attached to the pessary provides high comfort for the user and high data reliability and is therefore advantageous for the method and system of the present disclosure. The method and system of the present disclosure, however, may be used with other sensors that measure continuous series of resistance data points and, optionally, of body core temperature data points inside the body or measure series of temperature values at other places of the body even though the temperature measurement in other places may be less precise.
[0039] The resistance sensor comprises at least two resistance electrodes El, E2 that are arranged in the sensor device 10. The resistance electrodes may be arranged at the surfaces of the sensor device and may be configured to come in contact with the cervical mucus, when the pessary is placed in the vagina. The electrodes may be made from a metal material. Gold or other inert metals may be applied. The electrodes may used for resistance and/or for impedance measurements.
[0040] Fig. 2 shows an example of a circuit diagram that can be used for measuring the resistance. The sensor device 10 comprises a microcontroller 12 that is connected to a capacitor C by contact Cl and contact C2. The capacitor C can be charged in both polarities depending on the polarity applied to contact Cl and C2. For example, a microcontroller voltage of 3V can be used to directly charge the capacitor C. In other examples the microcontroller may control an external power supply to charge the capacitor C to higher
voltages. The charged capacitor C is connected to both electrodes El and E2 such that the capacitor can discharge via the electrodes El and E2 if both electrodes are connected. In use, an electrical connection is present via cervical mucus, other body fluids or intrabody media, the electrodes are connected to. These intrabody media have a certain resistance Rb that can be measured by determining a discharging time with the microcontroller 12.
[0041] Fig. 3 shows examples of corresponding discharging curves. The capacitor C is charged with different polarities to a max voltage Uc and subsequently an average discharging time is recorded. The decay in voltage is an exponential decay and a threshold voltage is defined. The time is determined by which the capacitance voltage drops below the threshold voltage. In the example of Fig. 3, the threshold voltage is 1/3 of the maximal voltage Uc but other thresholds may be used as well. The measurement may be repeated several times and with different polarities to obtain an average discharging value. Measured values with unreasonable results may be removed or other correction methods may be applied.
[0042] It is advantageous, to monitor the resistance and the optional temperature continuously over the whole day, during night and day, and, if possible, over the entire menstrual cycle of the female, resistance data points are taken in pre-determined time intervals and a series of resistance data points is formed from consecutive data points. A continuous resistance data curve can be evaluated from these resistance data points representing the actual resistance in the vagina of the female. In some applications, a series of temperature data points and, optionally, a continuous temperature data curve is evaluated from the temperature data points.
[0043] Examples for continuous data curves of temperature data points and resistance data points are shown in Figures 4a and 4b, respectively. 288 temperature data points per day were measured and recorded continuously every 5 minutes over a menstrual cycle (about 30 days or more). The pre-determined time interval is 5 minutes in this example but can be varied. Resistance data points were measured and recorded in the same time interval as the temperature data points for convenience.
[0044] Figure 4 a and b show an example of a biphasic female cycle in which ovulation occurred. Fig. 4a shows a series of temperature data points that vary during day and night times and that depend not only on the hormone status, but also on other activities and health parameters of the user. Several approaches were made to derive basal temperatures from temperature data curves. Some more advanced method for the determination of a hormone status based on body core temperature curves are described in WO 2015/044 398 Al and in PCT/EP2020/064613, the entire contents of which are incorporated by reference herein. These methods may be used to determine a hormone status based on the temperature data. In the example shown in Fig. 4a, the increase in basal temperature, i.e. the lowest temperature within a 24 hours period can be seen by eye. This increase corresponds to an increase in active progesterone in the vagina. Analysis of temperature amplitudes and a reduction in daily temperature amplitude, i.e. the difference between daily temperature maximum and daily temperature minimum provides even more reliable results on the amount of active progesterone in the vaginal channel. This is explained in detail in PCT/EP2020/064613.
[0045] Fig. 4b shows an example of impedance data measured simultaneously to the temperature curve of Fig. 2a at the same place in the vagina channel. The impedance may relate to the impedance of the cervical mucus or to vaginal tissue or to a combination thereof. The impedance data of Fig. 4b show a significant increase on day 7 and 8. The impedance is constantly increasing over more than 24 hrs. to a level far above the usual fluctuations. The inventors found that this increase is correlated to the distribution of estrogen, in particular of estradiol, into the body. The presence of estrogen may increase the amount or water in the cell or which may alter the structure of vaginal secrets like the cervical mucus which, in turn, alter the impedance. In the example of the present disclosure, the impedance is measured in the vagina, which is a measure for the effect of estrogen in the vagina. In other words, the present disclosure provides a method for determining an estrogen response in the vagina.
[0046] In the particular example shown in Fig. 4, impedance increases, in the particular example shown, about 24 hours prior to the release of progesterone, indicating that estrogen was released and that ovulation is probable to occur shortly after. The time window between increase of impedance and the response to progesterone may differ from cycle to cycle and may differ from woman to woman. The time window can be 24 hours or even less an can be longer up to several days in other examples. However, the increase in impedance indicates that ovulation will occur within short. If the temperature is evaluated in parallel, a low temperature may indicate the window of ovulation and a rise in temperature or reduction in temperature amplitude may indicate the increase of progesterone after ovulation.
[0047] Fig. 5 shows an example of text book curves showing a typical concentration of the hormones estrogen, progesterone, LH, and FSH in a female. This figure indicates the amount of progesterone present in the body. In contrast, the impedance and temperature data shown in Figs. 4 indicate the actual response of the female body to the present of the hormones. That means that only active hormones are measured. Hormones that, for example, if hormones can not bind to corresponding receptors or in cases of a disfunction of the receptors or subsequent signal cascades, the presence of estrogen will have no or only reduced effect. This may be detected by the present disclosure and appropriate treatment may be triggered.
[0048] Fig. 6 shows a comparison of different cycle types. The left hand figures indicate a normal biphasic cycle where ovulation occurred. This cycle is similar to the cycle shown in Fig. 4. The right-hand figures show temperature date and impedance data (lower curve) for a monophasic cycle, i.e. a cycle in which no ovulation occurs. In this example, no increase in impedance is observed indicating that no estrogen was released or that release of estrogen did not have any effect. Temperature data in the upper curve do not show a rise in temperature or a decrease in temperature amplitude indicating that no progesterone was released. In this case no ovulation occurred.
[0049] We have shown examples of how impedance can be used to reflect the presence or the effect of estrogen in the female cycle by using examples of clear biphasic and clear monophasic cycles for illustrative purposes. It is obvious to a person skilled in the art that not all female circles are that evident and that more detailed information about the present status of estrogen and/or progesterone can be obtained by further analysis of the data.
[0050] The examples and description above are given with respect to use of the present disclosure with a female human being. While there are numerous applications, such as female cycle diagnosis, fertility diagnosis, contraception etc., the description is not limited to use with human beings. The present description may equally be used with any mammals.
Claims
1. A method for determining a status of a female cycle of a female, the method comprising:
- determining a continuous series of temperature data points relating to a body temperature of the female;
- determining a status of a second biomarker based on the continuous series of temperature data points;
- determining a continuous series of resistance related data points relating to an electrical resistance in a vagina of the female;
- determining a status of a first biomarker based on the continuous series of resistance related data points; and correlating the status of the first biomarker with the status of the second biomarker and indicating the status of the female cycle based on the correlation between the status of the first biomarker and the status of the second biomarker.
2. The method of claim 1, wherein determining the status of a first biomarker based on the continuous series of resistance data points comprises identifying, in the continuous series of resistance data points, if a rise in resistance occurs that is higher than a predetermined value.
3. The method of claim 1 or 2, wherein the second biomarker is a progesterone level.
4. The method of any one of the preceding claims, wherein the first biomarker is an estrogen level.
5. The method of claim 4, wherein the estrogen level is an estradiol level.
6. The method of any of the preceding claims, wherein the resistance in the vagina is at least one of the resistance measured in the cervical mucus, a vaginal tissue of the female or any combination thereof.
The method of any of the preceding claims, wherein the determining the continuous series of resistance data points comprise measuring a plurality of resistance data points per hour continuously over a plurality of days. The method of any of claims 2 to 7, wherein the identifying, in the continuous series of resistance data points, if a rise in resistances occurs, comprises identifying if the rise occurs for at least a first time interval. A system for determining a biomarker status of a female, the system comprising a sensor device comprising a temperature sensor for determining and recording a series of temperature data points relating to a body temperature of the female and an electrical resistance sensor for determining and recording a series of resistance data points in the vagina of the female; an analysing tool for analysing the series of temperature data points and for analysing the series of resistance data points, wherein the series of temperature data points and the series of resistance data points are transferred from the sensor device to the analysing tool, whereinthe analysing tool is configured for performing the steps of:
- determining a status of a second biomarker based on the continuous series of temperature data points;
- determining a status of a first biomarker based on the continuous series of resistance data points, and correlating the status of the first biomarker with the status of the second biomarker and indicating the status of the female cycle based on the correlation. A method for determining a status of a biomarker in a female, the method comprising: determining a continuous series of resistance related data points relating to electrical resistance in a vagina of the female;
identifying, in the continuous series of resistance related data points, if a rise in electrical resistance occurs that is higher than a predetermined value; and correlating the rise in electrical resistance to an increased level of a first biomarker in the female. The method of claim 10, wherein determining the status of a first biomarker based on the continuous series of resistance data points comprises identifying, in the continuous series of resistance data points, if a rise in resistance occurs that is higher than a predetermined value. The method of claim 10 or 11, wherein the first biomarker is an estrogen level. The method of any of claims 10 to 12, wherein the resistance in the vagina is at least one of the resistance measured in the cervical mucus, a vaginal tissue of the female or any combination thereof. The method of any of claims 10 to 13, wherein the determining the continuous series of resistance data points comprise measuring a plurality of resistance data points per hour continuously over a plurality of days. The method of any of claims 10 to 14, wherein the identifying, in the continuous series of resistance data points, if a rise in resistances occurs, comprises identifying if the rise occurs for at least a first time interval. A method for determining a status of a biomarker in an intrabody medium using a sensor device (10), the method comprising: charging a capacitor (C) in the sensor device (10); discharging the capacitor via two electrodes (El, E2), wherein the electrodes are in contact with the intrabody medium; determining a discharging time by which the charge of the capacitor is below a predetermined value (Uth); and
17
correlating the discharging time to an electrical resistance of the intrabody medium. The method of claim 16, further comprising repeating the steps of the method with charging the capacitor with the opposite polarity. The method of claim 16 or 17, further comprising repeating the steps of the method in pre-determined time intervals to obtain a series of resistance data points. The method of claim 18, further comprising repeating the steps of the measurements in pre-determined time intervals over a plurality of days to obtain a continuous series of resistance data points. The method of claim 19, further comprising: identifying, in the continuous series of resistance related data points, if a rise change in electrical resistance occurs that is higher than a predetermined value; and correlating the rise in resistance to an increase of a first biomarker in the intrabody medium. The method of claim 20, wherein the first biomarker is an estrogen level. The method of any one of claims 16 to 21, wherein the intrabody medium is a cervical mucus, a vaginal tissue of a female or a combination thereof. A sensor device (10) for determining a status of a biomarker in an intra body medium, the sensor device comprising: a capacitor (C) in the sensor device (10); a first electrode (El) connected to a first side of the capacitor; a second electrode (E2) connected to a second side of the capacitor;
18
a microcontroller (12) for determining a discharging time of the capacitor when the capacitor is discharged over an intra body resistance between the first electrode (El) and the second electrode (E2). 24. The sensor device of claim 23, further comprising a flexible pessary for insertion in a vagina of a female.
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WO2015044398A1 (en) | 2013-09-26 | 2015-04-02 | Vivosensmedical Gmbh | Ovulation determination |
WO2019199819A1 (en) * | 2018-04-09 | 2019-10-17 | Ryan Jeanna | Intravaginal system for menstrual cycle monitoring |
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